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    Clinical Trial Results:
    A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of VX-445 Combination Therapy in Subjects With Cystic Fibrosis (CF) Who Are Homozygous or Heterozygous for the F508del Mutation

    Summary
    EudraCT number
    2018-000185-11
    Trial protocol
    SE   DE   GB   CZ   BE   NL   AT   GR   FR   IT  
    Global end of trial date
    09 Jan 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Jul 2023
    First version publication date
    23 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-445-105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03525574
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue , Boston, Massachusetts, United States,
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002324-PIP01-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of VX-445 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who were homozygous or heterozygous for the F508del mutation.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    56 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 32
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 31
    Country: Number of subjects enrolled
    Austria: 13
    Country: Number of subjects enrolled
    Belgium: 32
    Country: Number of subjects enrolled
    Czechia: 6
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United States: 280
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Australia: 24
    Worldwide total number of subjects
    507
    EEA total number of subjects
    147
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    145
    Adults (18-64 years)
    362
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects from the parent studies VX17-445-102 (NCT03525444) and VX17-445-103 (NCT03525548) were enrolled in this study. A total of 507 subjects were enrolled in this study.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Treatment Period: ELX/TEZ/IVA
    Arm description
    Subjects received ELX 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hrs (q12h) in the treatment period for 192 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ELX/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    elexacaftor/tezacaftor/ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-445/TEZ/IVA TC, once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Number of subjects in period 1 [1]
    Treatment Period: ELX/TEZ/IVA
    Started
    506
    Completed
    354
    Not completed
    152
         Physician decision
    6
         Commercial Drug is Available for Subject
    48
         Death
    1
         Other
    58
         Adverse event
    15
         Lost to follow-up
    4
         Other non-compliance
    2
         Withdrawal of consent (not due to AE)
    18
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total 507 subjects were enrolled from the parent studies. One subject is enrolled but was not dosed in this study. Therefore, data for 506 subjects are reported in the subject disposition and baseline sections.
    Period 2
    Period 2 title
    Extension Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Extension Period: ELX/TEZ/IVA
    Arm description
    Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the extension period for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ELX/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    elexacaftor/tezacaftor/ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ELX/TEZ/IVA triple combination (TC), once daily in the morning.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received IVA once daily in the evening.

    Number of subjects in period 2 [2]
    Extension Period: ELX/TEZ/IVA
    Started
    11
    Completed
    0
    Not completed
    11
         Commercial Drug is Available for Subject
    10
         Other
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 507 subjects were enrolled in the parent studies on treatment period. However, only 11 subjects rolled over to extension period from treatment period of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period: ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hrs (q12h) in the treatment period for 192 weeks.

    Reporting group values
    Treatment Period: ELX/TEZ/IVA Total
    Number of subjects
    506 506
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.7 ( 10.7 ) -
    Gender categorical
    Units: Subjects
        Female
    251 251
        Male
    255 255

    End points

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    End points reporting groups
    Reporting group title
    Treatment Period: ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hrs (q12h) in the treatment period for 192 weeks.
    Reporting group title
    Extension Period: ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the extension period for 48 weeks.

    Primary: Treatment Period: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    Treatment Period: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    The Open-Label Safety Set (OL-SS) included all subjects who had received at least 1 dose of study drug in the OL study.
    End point type
    Primary
    End point timeframe
    From Day 1 up to Week 196
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for this endpoint.
    End point values
    Treatment Period: ELX/TEZ/IVA
    Number of subjects analysed
    506
    Units: subjects
        Subjects With TEAEs
    504
        Subjects With SAEs
    175
    No statistical analyses for this end point

    Primary: Extension Period: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    Extension Period: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [2]
    End point description
    The Open-label Extension Period Safety Set (OL-EP-SS) include all subjects who have received at least 1 dose of study drug in the Extension Period of the OL study.
    End point type
    Primary
    End point timeframe
    From Day 1 up to Week 52
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned. No statistical comparisons were planned for this endpoint.
    End point values
    Extension Period: ELX/TEZ/IVA
    Number of subjects analysed
    11
    Units: subjects
        Subjects With TEAEs
    7
        Subjects With SAEs
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Safety follow-up (up to Week 196 for Treatment period and up to Week 52 for Extension period)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Treatment Period: ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks.

    Reporting group title
    Extension Period: ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the extension period for 48 weeks.

    Serious adverse events
    Treatment Period: ELX/TEZ/IVA Extension Period: ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    175 / 506 (34.58%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Philadelphia positive acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical deconditioning
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular torsion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    11 / 506 (2.17%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 19
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rales
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sputum increased
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia nervosa
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anger
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterovirus test positive
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 506 (0.99%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 506 (0.99%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture of penis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary contusion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access site pain
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis lung
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postural orthostatic tachycardia syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Miller Fisher syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic nervous system imbalance
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    4 / 506 (0.79%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    6 / 506 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyclic vomiting syndrome
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    9 / 506 (1.78%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    2 / 25
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    5 / 506 (0.99%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngo-oesophageal diverticulum
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    5 / 506 (0.99%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Thyroid mass
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    83 / 506 (16.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    3 / 150
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    4 / 506 (0.79%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    7 / 506 (1.38%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 506 (1.19%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    4 / 506 (0.79%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    3 / 506 (0.59%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 506 (0.40%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 506 (0.20%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Period: ELX/TEZ/IVA Extension Period: ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    501 / 506 (99.01%)
    7 / 11 (63.64%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    118 / 506 (23.32%)
    0 / 11 (0.00%)
         occurrences all number
    205
    0
    Influenza like illness
         subjects affected / exposed
    33 / 506 (6.52%)
    0 / 11 (0.00%)
         occurrences all number
    43
    0
    Malaise
         subjects affected / exposed
    26 / 506 (5.14%)
    0 / 11 (0.00%)
         occurrences all number
    42
    0
    Pain
         subjects affected / exposed
    37 / 506 (7.31%)
    0 / 11 (0.00%)
         occurrences all number
    43
    0
    Pyrexia
         subjects affected / exposed
    147 / 506 (29.05%)
    0 / 11 (0.00%)
         occurrences all number
    235
    0
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    83 / 506 (16.40%)
    0 / 11 (0.00%)
         occurrences all number
    164
    0
    Seasonal allergy
         subjects affected / exposed
    45 / 506 (8.89%)
    0 / 11 (0.00%)
         occurrences all number
    56
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    166 / 506 (32.81%)
    1 / 11 (9.09%)
         occurrences all number
    315
    1
    Cough
         subjects affected / exposed
    231 / 506 (45.65%)
    0 / 11 (0.00%)
         occurrences all number
    567
    0
    Dyspnoea
         subjects affected / exposed
    62 / 506 (12.25%)
    0 / 11 (0.00%)
         occurrences all number
    104
    0
    Haemoptysis
         subjects affected / exposed
    82 / 506 (16.21%)
    1 / 11 (9.09%)
         occurrences all number
    188
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    37 / 506 (7.31%)
    0 / 11 (0.00%)
         occurrences all number
    52
    0
    Nasal congestion
         subjects affected / exposed
    113 / 506 (22.33%)
    0 / 11 (0.00%)
         occurrences all number
    184
    0
    Productive cough
         subjects affected / exposed
    61 / 506 (12.06%)
    0 / 11 (0.00%)
         occurrences all number
    91
    0
    Respiration abnormal
         subjects affected / exposed
    33 / 506 (6.52%)
    0 / 11 (0.00%)
         occurrences all number
    47
    0
    Rhinorrhoea
         subjects affected / exposed
    76 / 506 (15.02%)
    0 / 11 (0.00%)
         occurrences all number
    108
    0
    Sinus congestion
         subjects affected / exposed
    62 / 506 (12.25%)
    0 / 11 (0.00%)
         occurrences all number
    102
    0
    Sputum increased
         subjects affected / exposed
    127 / 506 (25.10%)
    0 / 11 (0.00%)
         occurrences all number
    229
    0
    Wheezing
         subjects affected / exposed
    33 / 506 (6.52%)
    0 / 11 (0.00%)
         occurrences all number
    54
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    34 / 506 (6.72%)
    0 / 11 (0.00%)
         occurrences all number
    39
    0
    Anxiety
         subjects affected / exposed
    38 / 506 (7.51%)
    0 / 11 (0.00%)
         occurrences all number
    48
    0
    Depression
         subjects affected / exposed
    40 / 506 (7.91%)
    0 / 11 (0.00%)
         occurrences all number
    46
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    72 / 506 (14.23%)
    0 / 11 (0.00%)
         occurrences all number
    91
    0
    Bacterial test positive
         subjects affected / exposed
    50 / 506 (9.88%)
    0 / 11 (0.00%)
         occurrences all number
    82
    0
    Blood bilirubin increased
         subjects affected / exposed
    31 / 506 (6.13%)
    0 / 11 (0.00%)
         occurrences all number
    48
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    72 / 506 (14.23%)
    0 / 11 (0.00%)
         occurrences all number
    101
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    26 / 506 (5.14%)
    0 / 11 (0.00%)
         occurrences all number
    37
    0
    Pulmonary function test decreased
         subjects affected / exposed
    30 / 506 (5.93%)
    0 / 11 (0.00%)
         occurrences all number
    35
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    45 / 506 (8.89%)
    0 / 11 (0.00%)
         occurrences all number
    50
    0
    Weight decreased
         subjects affected / exposed
    32 / 506 (6.32%)
    0 / 11 (0.00%)
         occurrences all number
    32
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    68 / 506 (13.44%)
    0 / 11 (0.00%)
         occurrences all number
    82
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    21 / 506 (4.15%)
    1 / 11 (9.09%)
         occurrences all number
    23
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    11 / 506 (2.17%)
    1 / 11 (9.09%)
         occurrences all number
    12
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    38 / 506 (7.51%)
    0 / 11 (0.00%)
         occurrences all number
    49
    0
    Headache
         subjects affected / exposed
    178 / 506 (35.18%)
    0 / 11 (0.00%)
         occurrences all number
    335
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    31 / 506 (6.13%)
    0 / 11 (0.00%)
         occurrences all number
    42
    0
    Abdominal pain
         subjects affected / exposed
    76 / 506 (15.02%)
    0 / 11 (0.00%)
         occurrences all number
    106
    0
    Abdominal pain upper
         subjects affected / exposed
    49 / 506 (9.68%)
    0 / 11 (0.00%)
         occurrences all number
    72
    0
    Constipation
         subjects affected / exposed
    72 / 506 (14.23%)
    0 / 11 (0.00%)
         occurrences all number
    97
    0
    Diarrhoea
         subjects affected / exposed
    89 / 506 (17.59%)
    0 / 11 (0.00%)
         occurrences all number
    120
    0
    Nausea
         subjects affected / exposed
    91 / 506 (17.98%)
    0 / 11 (0.00%)
         occurrences all number
    141
    0
    Vomiting
         subjects affected / exposed
    67 / 506 (13.24%)
    0 / 11 (0.00%)
         occurrences all number
    96
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    49 / 506 (9.68%)
    0 / 11 (0.00%)
         occurrences all number
    57
    0
    Rash
         subjects affected / exposed
    57 / 506 (11.26%)
    0 / 11 (0.00%)
         occurrences all number
    78
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    71 / 506 (14.03%)
    0 / 11 (0.00%)
         occurrences all number
    106
    0
    Back pain
         subjects affected / exposed
    51 / 506 (10.08%)
    0 / 11 (0.00%)
         occurrences all number
    60
    0
    Myalgia
         subjects affected / exposed
    33 / 506 (6.52%)
    0 / 11 (0.00%)
         occurrences all number
    38
    0
    Neck pain
         subjects affected / exposed
    9 / 506 (1.78%)
    1 / 11 (9.09%)
         occurrences all number
    9
    1
    Pain in extremity
         subjects affected / exposed
    34 / 506 (6.72%)
    0 / 11 (0.00%)
         occurrences all number
    46
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    168 / 506 (33.20%)
    0 / 11 (0.00%)
         occurrences all number
    208
    0
    Cystitis
         subjects affected / exposed
    8 / 506 (1.58%)
    1 / 11 (9.09%)
         occurrences all number
    13
    1
    Gastroenteritis
         subjects affected / exposed
    31 / 506 (6.13%)
    0 / 11 (0.00%)
         occurrences all number
    34
    0
    Hordeolum
         subjects affected / exposed
    18 / 506 (3.56%)
    1 / 11 (9.09%)
         occurrences all number
    23
    1
    Influenza
         subjects affected / exposed
    63 / 506 (12.45%)
    0 / 11 (0.00%)
         occurrences all number
    72
    0
    Lower respiratory tract infection
         subjects affected / exposed
    7 / 506 (1.38%)
    1 / 11 (9.09%)
         occurrences all number
    7
    1
    Nasopharyngitis
         subjects affected / exposed
    154 / 506 (30.43%)
    0 / 11 (0.00%)
         occurrences all number
    335
    0
    Pharyngitis
         subjects affected / exposed
    37 / 506 (7.31%)
    0 / 11 (0.00%)
         occurrences all number
    54
    0
    Rhinitis
         subjects affected / exposed
    50 / 506 (9.88%)
    0 / 11 (0.00%)
         occurrences all number
    110
    0
    Sinusitis
         subjects affected / exposed
    76 / 506 (15.02%)
    1 / 11 (9.09%)
         occurrences all number
    126
    1
    Upper respiratory tract infection
         subjects affected / exposed
    120 / 506 (23.72%)
    1 / 11 (9.09%)
         occurrences all number
    223
    1
    Urinary tract infection
         subjects affected / exposed
    43 / 506 (8.50%)
    0 / 11 (0.00%)
         occurrences all number
    53
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    36 / 506 (7.11%)
    0 / 11 (0.00%)
         occurrences all number
    52
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    27 / 506 (5.34%)
    0 / 11 (0.00%)
         occurrences all number
    37
    0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    224 / 506 (44.27%)
    3 / 11 (27.27%)
         occurrences all number
    548
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 506 (5.14%)
    0 / 11 (0.00%)
         occurrences all number
    29
    0
    Hypoglycaemia
         subjects affected / exposed
    33 / 506 (6.52%)
    0 / 11 (0.00%)
         occurrences all number
    42
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2018
    Updated the study drug regimen to include ivacaftor in place of VX-561 (deuterated ivacaftor), added the number of tablets subjects will receive and tablet strength, and updated guidance on missed doses to account for every 12 hours (q12h) dosing of ivacaftor; Updated statistical analysis plan section for clarity.
    19 Jul 2018
    Updated study drug interruption and stopping rules (removed exclusion criteria of isolated total bilirubin elevations).
    09 Aug 2018
    Added guidance on concomitant dosing of VX-445/TEZ/IVA with P-glycoprotein (gp) and CYP2C9 substrates based on medicines and healthcare products regulatory agency (MHRA) request.
    08 Nov 2018
    Clarified analysis plan for baseline definition and number of pulmonary exacerbations.
    17 Dec 2019
    Removed organic anion transporting polypeptides (OATP) 1B1 substrates from prohibited medications list; Added guidance on concomitant dosing of VX-445/TEZ/IVA with OATP1B1, OATP1B3, P-gp, and CYP2C9 substrates; Removed rate of change in percent predicted forced expiratory volume in 1 second (ppFEV1) from Additional Endpoints.
    23 Jun 2020
    Extended the Treatment Period to evaluate the long-term efficacy of VX-445/TEZ/IVA beyond 96 weeks of treatment.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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